Extended release drugs are the next generation medical therapy

To determine which types of topical medications are best for patients, ophthalmologists need to look into what is truth and what is inaccurate regarding preservatives.

Boston—Topical ophthalmic medication preservatives are not benign, but may have adverse consequences for the ocular surface, the success of bleb-dependent procedures, and the trabecular meshwork.

“There is excellent evidence in the literature to support the claim that alternatively preserved and non-preserved medications are more gentle than medications preserved with benzalkonium chloride,” said Douglas Rhee, MD, associate professor of ophthalmology at Harvard Medical School in Boston. (Editor's Note: Dr. Rhee has recently been named chairman of the Department of Ophthalmology and Visual Sciecnes at Case Western Reserve University School of Medicine and University Hospitals' Case Medical Center, Cleveland, where he is expected to start this month.)

Topical ophthalmic medications typically come in three forms, he said. The most common formulation uses benzalkonium chloride as a preservative.

These medications are usually less expensive compared with other formulations and are the agents preferred—and sometimes required—by third-party payers.

Alternatively preserved medications typically use one of two preservatives:

Sofzia, which is an ionic buffer containing borate, worbitol, polylene, glycol and zinc.

Preservative free formulations are often referred to as non-preserved medications.

Preservative versus non-preserved meds

There is ample evidence to take into consideration when deciding on the proper medications, which claim those preserved with alternative agents are gentler to ocular tissues, Dr. Rhee said.

However, the evidence is less convincing when it comes to the potential effect of preservatives on bleb-dependent trabeculectomies and the trabecular meshwork.

The primary factor is that ophthalmic drugs can have adverse effects on ocular tissue.

“It is certainly true that pharmacologic agents themselves have an effect on ocular tissues,” Dr. Rhee said. “That drug-related effect is unavoidable, at least when you are using a topical delivery system.

“We may eventually get around surface disease issues and trabeculectomy issues by going to a different, non-topical delivery route . . . but those systems are still in development and testing,” he said.

Various in vitro studies have confirmed that benzalkonium chloride can cause inflammation in the conjunctiva and that it is lethal to trabecular meshwork cells—both as a single agent and as a preservative in ophthalmic medications.

“There is very good evidence that preservatives, or at least benzalkonium chloride, does have a deleterious effect on the ocular surface,” Dr. Rhee said. “Whether there is a difference in ocular surface disease between non-preserved medication and alternatively preserved medications is less clear—there is not a lot of evidence either way—but when it comes to benzalkonium chloride, the evidence of ocular surface disease is convincing.

“There is little question, based on my own clinical experience, that alternatively preserved and non-preserved agents are more gentle, better tolerated and induce fewer symptomatic side effects compared to the same drugs preserved with benzalkonium chloride,” he said.

There is also evidence which shows preserved topical medication can reduce the success rate of trabeculectomy surgeries that use a filtering bleb.

The problem, Dr. Rhee said, is that benzalkonium chloride increases inflammation in the conjunctiva. Topical ophthalmic medications also induce inflammation in the conjunctiva.

Looking further

The degree of inflammation that is due to the medications versus the inflammatory effects of preservatives is difficult to tease out. However, rabbits treated with non-preserved timolol had less conjunctival inflammation than similar rabbits given preserved timolol.

Those experimental findings support clinical observations that patients treated with non-preserved timolol for more than 1 year had more normal cytology than similar patients treated with preserved latanoprost or timolol.

“There is excellent evidence that topically delivered glaucoma medications—preserved and possibly non-preserved—cause an increase in conjunctival inflammation,” Dr. Rhee said. “That has been shown using impression cytology, confocal microscopy, and conjunctival biopsy. The major confounder is the pharmacologic agents themselves.”

The good news is pre-treating with topical corticosteroids before surgery may reverse inflammation and increase success rates for bleb-dependent trabeculectomies, he said.

In vitro exposure to benzalkonium chloride and other preservatives kill cultured trabecular meshwork cells in a dose-dependent manner.

Dr. Rhee and others are actively investigating the potential in vivo effects of preservatives on the trabecular meshwork.

“If it is feasible clinically and economically, there is convincing evidence that non-preserved and alternatively preserved medications are better than benzalkonium chloride-preserved medications because they are more gentle and better tolerated,” he said. “Reducing those side effects is an important positive step because side effects are a major barrier to adherence.”

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